The overall goal of the proposed research is to determine the relationship of both specific gene variants and epigenetic modification of genes of the opioidergic, stress response, serotonergic, and dopaminergic systems in the brain of HIV-1 infected subjects with the progression of HIV-1 disease. Many individuals infected with HIV-1 suffer from comorbid psychiatric illnesses, including depression, anxiety, and impulsive behaviors. Host genetic factors-can modify HIV-1 infection and have been shown to affect the vulnerability to develop psychiatric illnesses. Opioids promote HIV-1 replication in immune and glial cells in vitro, presumably by increasing levels of the chemokine CCR5 (one of the coreceptors for HIV-1 entry into the cell) and by the suppression of host HIV-protective factors. The relationship between the genotype and expression patterns of the mu-opioid receptor gene, OPRM1, and CCR5 in brain samples obtained from the National NeuroAIDS Tissue Consortium will be investigated. Comorbid depression, anxiety, atypical stress responsivity, impulsivity, and risk-taking behaviors, of which drug abuse/addiction may be a manifestation, will be examined. To identify peripheral markers for the progression of HIV-1 infection, the role of epigenetic factors in both brain and lymphocytes from individuals characterized as to psychiatric comorbidity and abuse/addiction, which may modulate key genes related to infectivity and risk-taking, will be examined. In a large study using samples from the Women's Interagency HIV Study repository, we will investigate the relationship between polymorphisms in genes of the serotonergic, dopaminergic and opioidergic systems with HIV-1 infection progression. The relationship of these variants with impulsivity and risk-taking to HIV-1 disease progression will be examined. Clarifying the functional relevance of polymorphisms associated with susceptibility to complex disorders such as psychiatric illnesses and abuse/addiction may provide the foundation for future clinical studies. Also, these studies may identify the role of genetic variants and epigenetic mechanisms in the progression of HIV- 1 infection and may point to targets for pharmacotherapy in HIV-1 disease with psychiatric comorbidity. The information gained from this research should help to alleviate the suffering of HIV-1 infection with comorbid psychiatric diseases.